FDA has found the sole clinical trial for IDM Pharma's Junovan (mifamurtide) neither robust nor significant, according to briefing material prepared for the Oncologic Drugs Advisory Committee's May 9 meeting to review the NDA.

According to FDA reviewers, the applicant failed to demonstrate that mifamurtide (muramyl tripeptide phosphatidyl ethanolamine, MTP-PE) provides substantial evidence of efficacy for the proposed indication for the treatment of newly diagnosed respectable high grade osteosarcoma following surgical resection in combination with multiple agent chemotherapy.

Irvine, Calif.-based IDM is supporting its claim for the efficacy of MTP-PE based on the outcome of the non-metastatic and respectable osteosarcoma cohort of patients in a single study (INT 0133) of approximately 600 children and young adults.

In the trial, when added to standard regimen of cisplatin, methotrexate and doxorubicin, MTP-PE failed to result in superior disease-free survival; an experimental arm containing ifosfamide was not superior to the standard regimen "and the observed trend suggested poorer DFS"; and the ifosfamide regimen plus MTP-PE was not superior to the standard regimen, FDA said.

FDA took issue with many aspects of the trial design, which was not discussed with the agency prior to initiation.

The study, which did not explicitly specify primary or secondary endpoints, failed to demonstrate all the goals for which it was designed.

FDA said the findings were not robust, "as demonstrated by lack of consistency across chemotherapeutic regimens, and are influenced by patients who were removed from study treatment prior to initiation of MTP-PE, by discrepancies between data in the case report forms and the electronic datasets, by lack of clarity on the timing of interim and final analyses, and by lack of a systematic and comprehensive approach to data collection over time."

Both FDA and the authors who published the study results in the Journal of Clinical Oncology in 2005 concluded that results could not be pooled across study arms because of the qualitative differences in effects on DFS when MTP-PE was added to the two chemotherapy regimens, and because results stemmed from a comparison of the addition of MTP-PE to a chemotherapy regimen that performed worse than the standard regimen.

"Even if one concludes that this analytic approach is valid, the results are not robust, such that using FDA's modified dataset ... the result is not significant," the agency's briefing documents state.

The advisory committee will address the following questions: "In light of the qualitative differences in outcome between the three experimental study arms and the control arm, is the applicant's pooled analyses of INT 1033 DFS data appropriate to determine the efficacy of MTP-PE?" and "Do the results of the study INT 0133 provide substantial evidence for the efficacy of MTP-PE in the treatment of patients with respectable and non metastatic osteosarcoma? Are the effects on DFS sufficiently robust and so compelling to justify marketing approval of MTP-PE based on this single trial?"

Also on May 9, the advisory committee will review Miami-based DOR BioPharma's NDA for orBec (beclomethasone dipropionate) for Graft-versus-Host disease.

- Jamie Hammon (j.hammon@elsevier.com)

FDA Finds IDM Pharma’s Junovan Study Lacking

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